SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Flumazenil 0.1 mg/ml solution for injection.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 0.1 mg flumazenil.

1 ampoule with 5 ml contains 0.5 mg flumazenil.

1 ampoule with 10 ml contains 1 mg flumazenil.

Excipient: each ml of solution contains 3.8 mg sodium.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Flumazenil is indicated for the complete or partial reversal of the central

sedative effects of benzodiazepines. It may therefore be used in anaesthesia

and in the intensive care in the following situations:

In anaesthesia

-    Termination of hypnosedative effects in general anaesthesia induced and/or maintained with benzodiazepines in hospitalized patients.

-    Reversal of benzodiazepine sedation in short-term diagnostic and therapeutic procedures in ambulatory patients and hospitalized patients.

In intensive care situations

-    For the specific reversal of the central effects of benzodiazepines, in order to restore spontaneous respiration.

- For diagnosis and treatment of intoxications or overdose with only or mainly benzodiazepines.

For the reversal of conscious sedation induced with benzodiazepines in children > 1 year of age.

4.2 Posology and method of administration

Flumazenil must be administered intravenously by an anaesthesist or doctor with experience in anesthesiology. Flumazenil may be administered either undiluted or diluted.

For dilution, see section 6.6.

It can be administered together with other reanimation measures.

Adults

Anaesthesia

The initial dose is 0.2 mg administered i.v. in 15 seconds. If the desired degree of consciousness is not obtained within 60 seconds, a second dose of 0.1 mg can be administered. This may be repeated at 60-second intervals where necessary, up to a total dose of 1.0 mg. The usual dose is 0.3-0.6 mg, but may deviate depending on the patient’s characteristics and the benzodiazepine used.

Intensive Care

The recommended initial dose of flumazenil is 0.3 mg i.v. If the desired level of consciousness is not obtained within 60 seconds, a repeat dose of 0.1 mg may be administered. If necessary, this may be repeated at 60-second intervals up to a total dose of 2 mg.

If drowsiness recurs, a second bolus injection of flumazenil may be administered. An i.v. infusion of 0.1 - 0.4 mg per hour has also been shown to be useful. The dosage and the rate of infusion should be individually adjusted to the desired level of sedation.

If no clear effect on awareness and respiration is obtained after repeated dosing, it should be considered that the intoxication is not due to benzodiazepines.

Infusion should be discontinued every 6 hours to verify whether resedation occurs.

In the intensive care unit, in patients treated for a long period of time with high doses of benzodiazepines, the individually titrated injections of Flumazenil, slowly administered, should not produce withdrawal symptoms (see section 4.4).

Elderly

In the absence of data on the use of flumazenil in elderly patients, it should be noted that this population is generally more sensitive to the effects of medicinal products and should be treated with due caution.

Children above 1 year of age

For the reversal of conscious sedation induced with benzodiazepines in children > 1 year of age, the recommended initial dose is 10 micrograms/kg (up to 200 micrograms), administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds , further injection of 10 micrograms/kg may be administered (up to 200 micrograms) and repeated at 60-second intervals where necessary (a maximum of 4 times) to a maximum total dose of 50 micrograms/kg or 1 mg, whichever is lower. The dose should be individualised based on the patient’s response. No data are available on the safety and efficacy of repeated administration of flumazenil to children for re-sedation.

Because of the potential for resedation and respiratory depression children previously sedated with midazolam should be monitored at least 2 hours after flumazenil administration. In case of other sedating benzodiazepines, the monitoring time must be adjusted according to their expected duration.

Children under the age of 1 year

There are insufficient data on the use of flumazenil in children under 1 year. Therefore flumazenil should only be administered in children under 1 year if the potential benefits to the patient outweigh the possible risk.

Patients with renal or hepatic impairment

In patients with impaired hepatic function, the elimination of flumazenil may be delayed (see section 5.2) and therefore reduced dosage for the repeated doses (not for the initial dose) is recommended. No dosage adjustments are required in patients with renal impairment.

4.3. Contraindications

Flumazenil is contraindicated in patients:

- with hypersensitivity to the active substance or any of the excipients -who have been administered benzodiazepines for the treatment of a potentially life-threatening condition (e.g. increased intracranial pressure or status epilepticus). In mixed intoxications with benzodiazepines and tricyclic and/or tetracyclic anitdepressants, the toxicity of the antidepressants can be masked by protective benzodiazepine effects.

-In the presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular symptoms of severe intoxication with tricyclics/tetracyclics, Flumazenil should not be used to reverse benzodiazepine effects.

4.4. Special warnings and precautions for use

• Use in children for other indications than reversal of conscious sedation is not recommended as no controlled studies are available. The same applies for children below the age of 1 year.

•    Until sufficient data are available, flumazenil should only be administered to children below the age of 1 year if the risks to the patient (especially in the case of accidental overdose) have been weighed up against the benefits of the treatment.

•    Elimination may be delayed in patients with hepatic impairment.

•    The antagonistic effect of flumazenil is specific to benzodiazepines; an effect is therefore not to be expected if the 'non-awakening' is caused by other substances. If flumazenil is administered for anaesthesiology at the end of the operation, the effect of the peripheral muscle relaxants must first have disappeared. Because flumazenil generally has a shorter duration of action than the benzodiazepines and therefore sedation can re-occur, the clinical state of the patient must be monitored, preferably in the intensive care unit, until the effect of flumazenil is eliminated.

•    In high-risk patients the benefits of a benzodiazepine-induced sedation should be weighed up against the risks of rapid return to consciousness. In patients (e.g. with cardiac problems), maintenance of a certain degree of sedation during the early postoperative period may be preferable to complete consciousness.

•    Rapid injection of flumazenil should be avoided. In patients with high dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding Flumazenil administration, rapid injection of doses equal to or higher than 1 mg has led to withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions.

•    In patients who are anxious during the pre operative phase or patients who are known to suffer from chronic or transient anxiety, the dosage of flumazenil should be adjusted carefully.

•    However, after major surgery, the post operative pain should be considered and it may be preferable to keep the patient lightly sedated.

•    For patients who have been treated chronically with high doses of benzodiazepines, the advantages of the use of flumazenil should be carefully weighed up against the risk of withdrawal symptoms; if, despite careful dosing, withdrawal symptoms occur, treatment with low doses of benzodiazepines, titrated intravenously according to the patient’s response, may be considered if necessary.

•    Use of the antagonist is not recommended in patients with epilepsy who have been treated with benzodiazepines for a prolonged period. Although flumazenil exerts a slight intrinsic anti convulsant effect, the abrupt suppression of the protective effect of a benzodiazepine agonist can induce convulsions in epileptic patients.

•    In patients with severe brain injury (and/or instable intracranial pressure) who are being treated with flumazenil - to antagonise the effects of benzodiazepines -increased intracranial pressure may develop.

•    Particular caution is necessary when using flumazenil in cases of mixed-drug overdose. In particular in the case of an intoxication with benzodiazepines and cyclic antidepressants, certain toxic effects such as convulsions and cardiac arrhythmias, which are caused by these antidepressants but which emerge less readily on concomitant administration with benzodiazepines, are exacerbated on administration of flumazenil.

•    Patients who have received flumazenil for the reversal of benzodiazepine effects should be monitored for resedation, respiratory depression or other residual benzodiazepine effects for an appropriate period based on the dose and duration of effect of the benzodiazepine employed.

•    Flumazenil is not recommended for the treatment of benzodiazepine dependence or for the treatment of protracted benzodiazepine abstinence syndromes.

•    Panic attacks have been reported after the use of Flumazenil in patients with a history of panic disorder.

•    Due to the increased frequency of benzodiazepines tolerance and dependence in patients with alcoholism and other drug dependencies, Flumazenil should be used with caution in its population.

• This medicinal product contains approximately 3.8 mg sodium per ml of flumazenil solution for injection. This should be taken into consideration by patients on a controlled sodium diet.

4.5. Interaction with other medicinal products and other forms of interaction

Flumazenil antagonises the central effects of benzodiazepines by competitive interaction at receptor. The effects of non-benzodiazepine agonists that act via the benzodiazepine receptor, such as zopiclone, triazolopyridazine and others, are also blocked by flumazenil However, flumazenil does not block the effect of medicines that do not operate via this route. Interaction with other centrally acting substances has not been observed. The pharmacokinetics of benzodiazepines are not influenced by the antagonist flumazenil. Particular caution is necessary when using flumazenil in cases of accidental overdose since the toxic effects of other psychotropic medicinal products (especially tricyclic antidepressants) taken concurrently may increase with the subsidence of the benzodiazepine effect.

On administering flumazenil concomitantly with the benzodiazepines midazolam, flunitrazepam and lormetazepam, the pharmacokinetic parameters of flumazenil were unaffected.

There is no pharmacokinetic interaction between ethanol and Flumazenil.

4.6. Pregnancy and lactation

There are insufficient data on use in human pregnancy for an assessment of possible harmful effects and efficacy in the foetus. Caution is therefore required. To date, there is no evidence of harmful effects in animal studies. The efficacy in the foetus has not been investigated in animal studies.

It is not known whether flumazenil passes into breast milk. In emergency situations, however, the parenteral administration of flumazenil to a patient who is breastfeeding is not contraindicated.

4.7. Effects on ability to drive and use machines

Although patients are awake and conscious after administration of Flumazenil, they should be advised not to operate dangerous machinery or drive a vehicle during the first 24 hours, because the effect of the earlier administered benzodiazepine may recur.

4.8. Undesirable effects

The adverse events listed below have been reported. Adverse events usually subside rapidly without the need for special treatment.

Frequency categories are defined using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).

Immune systems disorders Common	Allergic reactions.
Psychiatric disorders Uncommon Not known	Anxiety*, fear* Withdrawal symptoms (e.g., agitation, anxiety, emotional lability, confusion, sensory distortions), following rapid injection of doses of 1 mg or more in patients with high-dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration (see section 4.4), panic attacks (in patients with a history of panic reactions), abnormal crying, agitation, aggressive reactions (the side effect profile in children is generally similar to that in adults. When flumazenil has been used for the reversal of conscious sedation, abnormal crying, agitation and aggressive reactions have been reported).
Nervous system disorders Not known	Vertigo, headache, agitation*, tremor. Seizures: particularly in patients known to suffer from epilepsy or severe hepatic impairment, mainly after long-term treatment with benzodiazepines or in cases of mixed-drug abuse).
Eye disorders Common	Diplopia, strabismus, lacrimation increased.
Cardiac disorders Uncommon	Palpitations*, tachycardia or bradycardia, extrasystole.
Vascular disorders Common Not known	Hypotension, orthostatic hypotension. Transient increased blood pressure (on awakening).
Respiratory, thoracic and mediastinal disorders Uncommon	Dyspnea, cough, nasal congestion.
Gastrointestinal disorders Common	Nausea, vomiting: during post-operative use, particularly if opiates have also been used.
Skin and subcutaneous tissue disorders Common Not known	Sweating Flushing.
General disorders and administration site conditions Common Not known	Fatigue, injection site pain. Chills*.

* following rapid injection, generally did not require treatment.

4.9. Overdose

In cases of mixed-drug overdose, particularly with cyclic antidepressants, toxic effects (such as convulsions and cardiac dysrhythmias) may emerge with the reversal of benzodiazepine effects by flumazenil.

There is very limited experience of acute overdose in humans with flumazenil.

There is no specific antidote for overdose with flumazenil. Treatment should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Even at dosages of 100 mg i.v., no symptoms of overdosage were observed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidotes.

ATC code: V03A B25

Flumazenil, an imidazobenzodiazepine, is a benzodiazepine antagonist which, by competitive interaction, blocks the effects of substances acting via the benzodiazepine-receptor. Neutralisation of paradoxal reactions of benzodiazepines has been reported.

According to experiments in animals, the effects of substances, which are not acting via the benzodiazepinereceptor (like barbiturates, GABA-mimetics and adenosinereceptor agonists), are not blocked by flumazenil. Non-benzodiazepine-agonists, like cyclopyrrolones (zopiclon) and triazolopyridazines, are blocked by flumazenil. The hypnosedative effects of benzodiazepines are blocked rapidly (within 30-60 seconds) after intravenous administration. Depending on the difference in elimination time between agonist and antagonist, the effect can recur after several hours. Flumazenil has possibly a slight agonistic, anticonvulsive effect. Flumazenil caused withdrawal, including convulsions in animals receiving long-term flumazenil treatment. Flumazenil is well tolerated, even in high doses.

5.2 Pharmacokinetic properties

Distribution

Flumazenil is a lipophilic weak base. Flumazenil is bound for approximately 50% to plasma proteins, from which two thirds are bound to albumin. Flumazenil is extensively divided over extravascular space. During the distribution phase plasma concentration of flumazenil decreases with a half life of 4-11 minutes. The distribution volume under steady-state conditions (Vss) is 0.9 - 1.1 L/kg.

Metabolism

Flumazenil is mainly eliminated through hepatic metabolism. The carboxilic acid metabolite was shown in plasma (in free form) and in urine (in free and conjugated form) to be the most important metabolite.

In pharmacological tests this metabolite has proved to be inactive as benzodiazepine agonist or antagonist.

Elimination

Almost no unchanged flumazenil is excreted in the urine. This indicates a complete metabolic degradation of the active substance in the body. Radiolabelled medicinal product is completely eliminated within 72 hours, with 90 to 95 % of the radioactivity appearing in the urine and 5 to 10 % in the faeces. Elimination is rapid, as is shown by the short half life of 40 to 80 minutes. The total plasma clearance of flumazenil is 0.8 to 1.0 L/hour/kg and can almost completely be attributed to hepatic metabolism.

The pharmacokinetics of flumazenil is dose-proportional within the therapeutic dose-range and up to 100 mg.

The intake of food during the intravenous infusion of flumazenil results in an increase of 50% of the clearance probably due to postprandial increase in liver perfusion.

Pharmacokinetics in special patient groups

Elderly:

The pharmacokinetics of flumazenil in elderly is not different from that in young adults.

Patients with impaired hepatic function:

In patients with a moderately to severely impaired liver function the half life of flumazenil is increased (increase of 70 - 210 %) and the total clearance is lower (between 57 and 74 %) compared to normal healthy volunteers.

Patients with impaired renal function:

Pharmacokinetics of flumazenil is not different in patients with impaired renal function or patients undergoing haemodialysis compared to normal healthy volunteers.

Paediatric population

In children above one year old, the half life elimination is shorter and the variability is higher than in adults, approximately of 40 min with a range 20 to 75 min). Clearance and volume of distribution, by kg of body weight are the same than in adults.

5.3 Preclinical safety data

Late prenatal as well as per- and postnatal exposure to flumazenil induced both behavioural alterations and an increase of hippocampal benzodiazepine receptor density in the rat offspring. The effect of these findings is not considered relevant if the product is used for a very short time as instructed.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Disodium edetate Glacial acetic acid Sodium chloride

Sodium hydroxide (10% m/V) for pH adjustment Hydrochloric acid (10% m/V) for pH adjustment Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except for those mentioned in section 6.6.

6.3 Shelf life

3 years.

Shelf life after first opening:

After first opening the medicinal product should be used immediately.

Shelf life after dilution:

Chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in a controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in the original package.

Do not refrigerate or freeze.

6.5 Nature and contents of container

Carton boxes with 1, 5, 6, 10 or 12 ampoules for injection.

Carton boxes with 1, 5, 6, 10 or 12 ampoules for injection.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

This medicinal product is for single use only and any unused solution should be discarded.

Please inspect the medicinal product visually. It should only be used if the solution is clear and practically free form particles.

When Flumazenil is to be used in infusion, it must be diluted prior to infusion. Flumazenil should only be diluted with sodium chloride 9 mg/ml (0.9 %) solution, dextrose 50 mg/ml (5 %) solution or Lactated Ringer's solution. Compatibility between flumazenil and other solutions for injection has not been established. Intravenous infusion solutions or syringes filled with a flumazenil solution should be discarded after 24 hours.

From a microbiological point of view the product should be used immediately after diluting. If the diluted product is not used immediately, the user/administrator is responsible for the terms of use employed and storage conditions for administration.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf Reykjavikurvegur 76-78,

220 HafnarfjorQur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0385

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/10/2009

10 DATE OF REVISION OF THE TEXT

28/10/2011